Monogenic hearing loss

Gene: MPZL2

Green List (high evidence)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 3 Mar 2022, 1:19 p.m. | Last Modified: 3 Mar 2022, 1:19 p.m.

Panel Version: 2.221

Comment on list classification: Promoting this gene from grey to amber with a recommendation of a green rating following GMS review. 15 cases reported, 3 different variants. Mouse model supports role of gene in hearing loss.

Created: 19 Nov 2020, 12:18 p.m. | Last Modified: 19 Nov 2020, 12:18 p.m.

Panel Version: 2.111

Associated with Deafness, autosomal recessive 111 #618145 (AR) in OMIM.

15 unrelated families reported but 5 are homozygous for variant c.72delA and 8 for c.220C>T:p.Gln74* in MPZL2. 2 others are compound heterzgyous. A total of 3 variants reported. Founder effects in the Turkey/Iran population were found. In the Korean population no founder effect was detected but the population freq of the c.220C>T:p.Gln74* variant is higher in the Korean/Japanese populations than in other populations. A mouse knockout showed early-onset progressive HI.

PMID: 32203226 Kim et al 2020 - screened 110 pediatric patients from 83 families with mild-to-moderate nonsyndromic SNHL (sporadic and recessive cases only) and identified 9 unrelated individuals with MPZL2-related deafness. 8 patients were homozygous for c.220C>T:p.Gln74*. 1 patient was compound het c.220C>T:p.Gln74*, c.463delG:p.Ala155Leufs*10 (NM_005797.3). They did not find a common haplotype associated with p.Gln74*, but the significantly higher minor allele frequency in Koreans (0.009439) and Japanese (0.01974) compared to overall population frequence (0.0003969) (Gnomad r2.1.1) suggests the allele could be a very old founder allele.

PMID: 29982980 - Bademci et al 2018 - report 3 unrelated consanganious families from Turkey and Iran with autosomal recessive nonsyndromic hearing and a loss and a loss-of-function variant (c.72delA) in MPZL2 which segregates with moderate hearing loss in the families. A shared haplotype flanking the variant in the families suggests a single founder.

PMID: 29961571 - Wesdorp et al 2018 - report 3 families with homozygous truncating variants in MPZL2. In 2 families (1 consanguineous Dutch, the original index case, 1 of Turkish origin (identified by phenotype matching) they identified a homozygous variant (c.72del (p.Ile24Metfs∗22). In a further family of Turkish origin, identified through previous WES, they found compound heterozygous variants in MPZL2 c.72del and c.220C>T (p.Gln74∗). Haplotype analysis of the c.72del MPZL2 alleles showed a shared a haplotype of at least 0.5 Mb, suggesting that it is a founder variant rather than a recurrent variant due to a mutational hotspot. Mpzl2-mutant mice showed early-onset progressive HI.

Created: 19 Nov 2020, 12:16 p.m. | Last Modified: 19 Nov 2020, 12:16 p.m.

Panel Version: 2.110

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Deafness, autosomal recessive 111 OMIM:618145; deafness, autosomal recessive 111 MONDO:0029142

Publications

• 29982980
• 29961571
• 32203226

Green List (high evidence)

16 individuals from 6 unrelated consanguineous families reported with bi-allelic variants in this gene.
Sources: Expert list

Created: 2 Jan 2020, 5:02 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Deafness, autosomal recessive 111, MIM#618145

Publications

• 29982980
• 29961571